Acetaminophen
Acetaminophen (Tylenol®/Paracetamol®) is the most common pain-relieving medication used during pregnancy, with an estimated 65 % to 75% of pregnant women in the United States using the medication, throughout all trimesters.
Acetaminophen is also considered to have the best safety profile compared to other pharmaceutical options, but more focused research is necessary.
Although numerous studies have indicated the drug is safe for all trimesters, recent studies have linked it to the development of various neurological developmental disorders such as autism spectrum disorder and attention-deficit/hyperactivity disorder. However, many other studies have not found these associations and researchers indicate these positive associations need to be interpreted with caution (see Concerns and Considerations).
It is recommended that women talk to their health care provider (HCP) before taking any acetaminophen – as is the general rule for all medications during pregnancy – and when needed, that women take the minimum effective dose for the least amount of time necessary.
Background
Acetaminophen has been used for decades as the first-line treatment for short-term relief of mild-to-moderate pain in pregnancy due to its safety profile. It is generally considered to be safer than other commonly used analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs; isuch as buprofen) or opiates.
Acetaminophen crosses the placenta and results in fetal exposure, but with no noticeable impact on fetal breathing or movements, and to date, no risk has been consistently associated with its use in any trimester.
Although there are research hurdles in studying acetaminophen's affects, it is estimated that nearly 60% of pregnant women have taken acetaminophen in the first trimester, and no consistent patterns have been identified (see Concerns and Considerations).
Pregnant women may use acetaminophen for many reasons during pregnancy: headache, fever, joint pain, back pain, or other acute injury. The extent of acetaminophen use during all of pregnancy may be as high as 75% in the United States and over 60% in Europe.
Although not completely understood, acetaminophen likely works by blocking the action of prostaglandin activity. Prostaglandins are a group of lipids made at sites of tissue damage or infection. They also control processes such as inflammation, blood flow, and the formation of blood clots, and help soften the cervix near labor. By blocking prostaglandin activity, acetaminophen therefore relieves symptoms of inflammation.
It is unclear what effects acetaminophen use may have on implantation, cervical ripening, or the initiation/length of labor, which all involve prostaglandin activity.
Dosing and Side Effects
Acetaminophen affects everyone differently, based on:
Dosage
Height, weight, and overall health
History of taking the drug
Whether other drugs are taken around the same time
Side effects from acetaminophen are rare, but can include:
Drowsiness and fatigue
An allergic reaction (rash, swelling)
Low blood pressure, fast heartbeat (usually from intravenous acetaminophen)
Thrombocytopenia (low number of platelet cells) and leukopenia (low number of white blood cells)
Liver and kidney damage (overdose)
In some products, such as cold and flu remedies or certain combination painkillers, acetaminophen is an included ingredient; the National Library of Medicine’s Pillbox database turns up nearly 2,600 OTC and prescription products that contain the drug.
Acetaminophen has an excellent safety profile when taken in appropriate doses for an appropriate amount of time. However, toxicity occurs relatively easily (in the liver) because the medicine is readily available and is in many different types of medications; individuals can accidentally take more than the recommended daily amount. Signs of acetaminophen toxicity include vomiting, abdominal pain, and liver failure, and can occur within hours to days.
Concerns and Considerations
UPDATE #2: The European Network of Teratology Information Services (ENTIS) released a position statement on October 4, 2021, in response to the statement below (Update #1).
"ENTIS holds the position that the evidence supporting an increased risk of untoward fetal effects and childhood neurodevelopment, including ASD & ADHD following in utero exposure to paracetamol (acetaminophen) is weak, inconsistent and to a large extent fundamentally flawed. ENTIS holds the position that paracetamol is the first-choice analgesic and antipyretic for pregnant women, but, as for any medication, should only be used when clearly indicated at the lowest dose and for the shortest possible duration." Read the full statement.
Note: According to their website, ENTIS is a global collaborative network of Teratology Information Services. Member organizations consist of medical doctors, pharmacists, genetic counsellors and scientists all working together with the primary aim of preventing birth defects and developmental disorders which arise as a consequence of maternal or paternal perinatal exposures.
UPDATE #1: A consensus statement signed by numerous scientific, research, and medical professionals was published on September 23, 2021. The main goal of the statement was to bring awareness to the scientific and medical communities that a focused research effort is necessary to provide better safety data regarding this very commonly used medication in pregnancy.
The authors noted that "...increasing experimental and epidemiological research suggests that prenatal exposure to [acetaminophen] might alter fetal development, which could increase the risks of some neurodevelopmental, reproductive and urogenital disorders."
The authors did NOT recommend that acetaminophen use should stop during pregnancy but that individuals should:
Use it only when medically indicated
Consult with a physician or pharmacist if they are uncertain whether use is indicated and before using on a long-term basis
Minimize exposure by using the lowest effective dose for the shortest possible time
The authors also noted..."We recognize the limitations of the existing epidemiological literature and the need for rigorous meta-analyses and therefore we call for a focused research effort."
For context, studying the possible negative pregnancy-related outcomes with the use of acetaminophen has many obstacles, most of which are similar to studying fever during pregnancy. Possible effects are very likely dependent on when acetaminophen was taken, how long it was taken, what it was taken for (i.e. fever or headache), as well as the woman’s history of taking the drug.
Acetaminophen is metabolized in the liver in adults and chronic use can cause liver toxicity. It is therefore possible the fetus metabolizes the drug differently than the pregnant woman (the liver is one of the last organs to fully develop), and that toxic levels in the fetus could build up more quickly, but this is not clear.
It is also not known what dosages of acetaminophen would need to be taken (or for how long) for this to begin to occur. Further, researchers still do not understand fully how acetaminophen works in the body, and the definition of chronic use has not been defined.
Evidence of problems with neurological development in children of mothers who took acetaminophen during pregnancy is accumulating, but studies differ widely in exposure and how the data was collected, which could affect results. This also makes it difficult to analyze these studies as a whole.
Neurological outcomes may be possible, as prostaglandin synthesis involves multiple essential processes underlying the function and development of the brain, such as long-term nerve impulse strength, learning, and cerebellar development. It is plausible acetaminophen may interfere with this process in utero, but this has not been thoroughly studied in humans.
Acetaminophen exposure (likely long-term) during pregnancy is linked with an increase in the risk of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), impaired motor development, behavioral disorders, and difficulty communicating.
ADHD is a common childhood disorder defined by inattention, hyperactivity, and impulsivity, affecting approximately 5% of children worldwide, often continuing into adulthood. Exposure to certain teratogens during pregnancy has been proposed as a possible causal factor.
Researchers have pointed out that not all studies have found these associations and caution needs to be used in the interpretation of those with positive findings.
Further, the above studies indicate the possibility of increased risk exists and does not mean that acetaminophen use will always lead to these disorders. Further, researchers are still learning about ASD and ADHD and how they are caused, which is currently assessed to be multifactorial (i.e genetics plus environmental factors).
Fever is also associated with ADHD, and many individuals take acetaminophen to reduce fever; this scenario is a current conundrum in the research community. For example, when a woman has a fever, takes acetaminophen, and the baby is born with a physical or mental birth defect, researchers do not know whether the fever or acetaminophen was responsible, possible factors of both, or neither.
Based on studies assessing risk of fever during pregnancy, fever appears to be more strongly associated with negative outcomes than either acetaminophen alone, or when acetaminophen was used with a fever (see Fever). Some researchers indicate that fever is the real teratogenic factor, and acetaminophen may reduce the risk of certain negative outcomes, but overall, this remains inconsistent.
It is important that women call their HCP anytime they have a fever during pregnancy so they can discuss the risks and benefits of taking anti-fever medication, especially if the fever is considered high.
A recent study identified a causal relationship between maternal acetaminophen intake and fetal ductus arteriosus (DA) constriction or closure (cardiac blood vessel that normally closes shortly after birth).
However, despite the broad usage of acetaminophen during pregnancy, DA prenatal closure is considered rare. Further, the dose of acetaminophen reported (or suggested) by researchers to close the DA in preterm infants is high, a dose unlikely to be taken by pregnant women. Other drugs are also being investigated as possible causes of DA prenatal closure.
Action
It is recommended that women talk to their HCP before taking any acetaminophen – as is the general rule for all medications during pregnancy. When needed, women should take the minimum effective dose for the least amount of time necessary.
When taking cold medications, women should read the label carefully, as many of these medications contain acetaminophen as well as other ingredients. It is easy to obtain too much acetaminophen when taking combination medications.
Women are also advised to call their HCP anytime they experience a fever during pregnancy. Fevers can be caused by common and manageable bacterial and viral infections, but they can also be caused by illnesses that need immediate treatment during pregnancy and are easily diagnosed through an office visit. Depending on the severity of the fever, HCPs may recommend a fever-reducing medication, such as acetaminophen (read more).
Resources
Fact Sheet: Acetaminophen (MotherToBaby.org)
FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy (U.S. Food and Drug Administration)